Clinical Report: The Staying Power of Small Molecules

Overview

Industry experts describe small molecules as an enduring and evolving drug modality rather than one displaced by cell therapies, antibody-drug conjugates, or RNA-based approaches. They cite oral administration, tissue penetration, manufacturing scalability, and advances in medicinal chemistry as continuing advantages, while noting emerging applications such as protein degradation.

Background

Small molecules remain established medicines, and a related article reports that they represented around 90% of approved medicines and 75% of new medicines approved in the United States in 2020. The source experts contrast their properties with those of newer modalities while emphasizing that different approaches may suit different biological targets and patient needs. Oral administration and access to intracellular targets or the central nervous system are highlighted as relevant features. The article also describes advances in computational methods, medicinal chemistry, and protein degraders as extending small-molecule development.

Data Highlights

Key Findings

• Dajun Yang identifies oral administration as an advantage for patients who may receive long-term treatment and notes that small molecules can cross the blood-brain barrier, unlike many larger modalities.
• Yang reports that Ascentage Pharma’s approved olverembatinib and lisaftoclax are oral therapies, and that its BTK degrader is advancing into global Phase I trials; the degrader is designed to eliminate the target protein rather than inhibit it.
• Peng Lu cites oral dosing, scalable manufacturing, broad tissue penetration, and lower immunogenicity risk relative to more complex modalities as small-molecule attributes; he also points to medicinal chemistry and structure-based design advances in potency and selectivity.
• Daniel Vitt highlights intracellular targets, including Nurr1 in multiple sclerosis, as settings where small molecules may be practical or the only viable option; he describes vidofludimus calcium as an investigational oral example.
• Ann Cleeves describes computational modelling and medicinal chemistry as tools for optimizing small molecules and complex macrocycles, citing Merck’s bridged PCSK9 macrocyclic MK-0616 (Enlicitide) as an example.
• A related article reports that small molecules accounted for around 90% of approved medicines and 75% of new medicines approved in the United States in 2020.

Clinical Implications

The experts frame modality selection as dependent on the biological target and patient needs, rather than as competition between drug classes. They identify oral administration, intracellular or central nervous system access, and manufacturing scalability as considerations when evaluating small-molecule approaches; the article does not provide comparative clinical outcome data for these attributes.

Conclusion

The source presents small molecules as an established modality whose applications continue to expand through advances in design and approaches such as targeted protein degradation. Its experts emphasize selecting modalities according to the therapeutic context.

Related Resources & Content

1. The Medicine Maker, 2025 — Small Molecules; Global Challenges
2. The Medicine Maker, 2021 — A Reawakening of Small Molecule Drug Development
3. The Medicine Maker, 2021 — Small Molecules: Expert Insight
4. the medicine maker — Small Molecules, Sizable Market Opportunities
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